We are interested in understanding the role of IL-6 in breast tumor growth and metastasis. Recent studies have linked IL-6 as a potent growth factor in estrogen receptor (ER) positive breast cancers. Studies from our lab and others have shown that IL-6 and pStat3 (a primary target of IL-6 signaling) are highly expressed in tumor emboli and on the edge of tumors - the invasive front. Also, our preliminary work on IL-6 and ER positive breast cancer cell lines has shown that when IL-6 is highly expressed, the levels of ER decrease. A principal mechanism by which the ER is regulated is through epigenetic changes including promoter methylation. We hypothesize that the IL-6/pStat3 pathway modulates ER expression, which alters breast cancer progression and responsiveness to therapy. The work proposed here will reveal a novel role for the IL-6/Jak/Stat3 pathway in modulating ER expression through epigenetic modification of the ER promoter and may lead to targeted therapies for breast cancer. My aims include: 1. Examine the role of IL-6/Stat3 mediated ER regulation. We will determine whether ER positive breast cancer cell lines can be made ER negative through Stat3 transcriptional repression of the ER1 gene and whether sustained IL-6 signaling can lead to loss of ER expression through pStat3/DNMT1 ER1 promoter methylation promoter methylation. 2. Determine whether a correlation exist between IL-6/pStat3 expression and ER levels in primary breast tumors with a focus on the distribution of these proteins on the leading edge and in tumor emboli. We are also interested in determining whether a) the -174G>C polymorphism is associated with higher IL-6 levels within the tumor and b) whether these tumors are ER negative. PUBLIC HEALTH RELEVANCE: The work proposed here will reveal a novel role for the IL-6/Jak/Stat3 pathway in modulating estrogen receptor (ER) expression. It would suggest that inhibition of this pathway would be a innovative approach to treating ER-negative breast tumors by rendering them ER-positive and allowing for effective treatment with anti-estrogens such as Tamoxifen. Thus, the consequences of this work may lead to the development of novel targeted therapies for patients with triple negative tumors in particular those which express high levels of IL-6.